Lynch Syndrome: A Multitude of Predispositions

The crucial message for the physician managing high-risk Lynch syndrome patients is to fully appreciate the fact that there is much more to Lynch syndrome than the endometrium and colon.

—Carrie L. Snyder, MSN, and Henry T. Lynch, MD

The current uncertainty regarding the relative frequencies of cancers of various anatomic sites in Lynch syndrome poses a difficulty in commenting on the syndrome’s overall cancer spectrum. It is even more vexing to address the order in which these cancers are prone to occur. What we do know is that there is an enormous lifetime risk of cancer at multiple anatomic sites in Lynch syndrome.

For example, when the syndrome was described in the 1960s, there was only limited knowledge about its cancer propensity, and primary focus was given to colorectal and endometrial cancers. Since those early reports, Lynch syndrome has become known to be the most frequent hereditary colorectal cancer–prone disorder, but is also now known to predispose to cancers of an almost unlimited number of other sites. These include some of the more frequently occurring cancers in the general population among women (namely, carcinoma of the breast) and among men (namely, prostate cancer).

Role of Mismatch Repair Genes

Approximately 5% of all endometrial cancers are the result of a hereditary predisposition. The majority of these hereditary cases are manifested in carriers of mismatch repair germline mutations consonant with Lynch syndrome.1 Lynch syndrome is the most common form of hereditary colorectal cancer, and most of the cancer screening publicity regarding the disorder focuses on the proven effectiveness of colonoscopy. While it is crucial to appreciate the importance of colonoscopy, most studies have found women with Lynch syndrome to have a higher risk for endometrial cancer than for colorectal cancer.

In fact, it has been estimated that both males and females harboring mismatch repair genes have upwards of a 69% lifetime risk for colorectal cancer, while women face up to a 71% risk of developing endometrial cancer.2,3 The risk of endometrial cancer subsequent to colorectal cancer is also increased.4 In addition, compared with the general population, women carrying a mismatch repair gene mutation have a 19-fold greater risk of developing ovarian cancer and a 4-fold increased risk of developing breast cancer.5

After Endometrial Cancer

Win et al6 set out to define the risk of subsequent cancers in women who have developed endometrial cancer and harbor a mismatch repair deleterious mutation. Their results showed that these women had the following 20-year risks of developing other cancers: “colorectal cancer (48%, 95% confidence interval [CI] = 35% to 62%); cancer of the kidney, renal pelvis, or ureter (11%, 95% CI = 3% to 20%); urinary bladder cancer (9%, 95% CI = 2% to 17%); and breast cancer (11%, 95% CI = 4% to 19%)....”

These rates were statistically significantly higher compared with women in the general population. The rate of ovarian cancer was not listed, suggesting that a hysterectomy with bilateral salpingo-oophorectomy was conducted at the time of each endometrial cancer diagnosis; however, this is not explicitly stated within the study. Given the excess of gynecologic cancer (endometrium and ovary) in Lynch syndrome and the respective limitations of their screening, which has virtually no benefit for ovarian cancer and is of only limited use in endometrial cancer, in our opinion a better choice is the option for prophylactic hysterectomy and bilateral salpingo-oophorectomy, once family is completed and the patient is fully accepting. Working with colleagues at MD Anderson Cancer Center,7 we have demonstrated the effectiveness of this approach.

Other Cancer Risks

In addition to endometrial cancer, cancers that occur in excess in germline mutation carriers for Lynch syndrome are the aforementioned colon and ovary cancers; cancers of the stomach, small bowel, pancreas, upper uroepithelial tract (ureter and renal pelvis), breast, and prostate; sebaceous adenomas, sebaceous carcinomas, multiple keratoacanthomas, and possibly other skin cancers in the Muir-Torre syndrome variant; and glioblastoma multiforme in the Turcot syndrome variant.

It was interesting to note that none of the 15 women who harbored a deletion in the EPCAM gene in the paper by Win and colleagues had a previous diagnosis of endometrial cancer and, therefore, all were excluded from this study. This is consistent with our finding of a more colon cancer–specific tumor spectrum in most families with an EPCAM deletion.8

Burden of Vigilance

The authors concluded that women with a mismatch repair gene mutation are at a significantly higher risk of developing subsequent Lynch syndrome–associated cancers. However, the site of the initial primary cancer does not appear to affect these risks.

These issues are clearly significant and add to the burden of vigilance for the physician. The crucial message for the physician managing high-risk Lynch syndrome patients is to fully appreciate the fact that there is much more to Lynch syndrome than the endometrium and colon. ■

Ms. Snyder is Cancer Genetics Nurse Specialist and Dr. Lynch is Professor and Chairman, Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, Nebraska.